Current antiretroviral therapy (ART) regimens for HIV-1 infection can block viral replication and provide substantial clinical benefit, but long-term therapy can be associated with significant toxicities and does not appear capable of eradicating the virus. Strategies to boost the immune system of infected individuals might provide a means to improve control of residual viral replication on ART, and eventually make it possible to reduce the requirement for ART. Development of effective immune-based therapies would be facilitated if the nature and magnitude of responses required to achieve the desired antiviral[ activity could be defined. Our group has extensive experience with the isolation, in vitro expansion, and adoptive transfer of human virus-specific CD8+ T cell clones as a strategy for establishing strong, functional CD8+ T cell responses, and with modification of CD8+ T cells to introduce genes that enhance T cell function, as well as with highly sensitive molecular techniques to detect viral reservoirs and persistent HIV replication in PBMC, lymphoid tissue, and mucosal tissue of HIV-infected individuals on potent ART. Our preliminary studies suggest that very high and sustained CD8+ responses to HIV might be achievable in HIV-infected individuals on potent ART with low viral burdens by infusion of HIV-specific CD8+ T cell clones followed by a brief course of low dose IL2. Thus, we propose to determine if providing such patients with a high frequency of functional differentiated CD8+ effector cells, specific for either gag or regulatory viral proteins expressed early in the viral life cycle, can contribute to containment of ongoing viral replication and reduction in persistent viral reservoirs. Additionally, one hallmark of HIV infection in comparison to other chronic viral infections is the decline of HIV-specific CD28+CD8+ T cells and accumulation of CD28+CD8+ T cells. The loss of expression of the CD28 costimulatory molecule, presumably from antigen-driven differentiation, has significant consequences on CD8+ T cell function, rendering the cells increasingly dependent on CD4+ T cell help. Our preliminary studies demonstrate that CD28 can be re-expressed in CD28+CD8+ T cells, and that such cells reacquire the ability to produce IL2 and proliferate following specific target recognition. Thus, we propose to genetically modify HIV-specific CD28+CD8+ effector cells and determine if transferred CD28+CD8+ T cells exhibit improved survival, function, and antiviral activity in individuals with detectable plasma viremia.